2-substituted-cinchona alkaloids

ABSTRACT

2&#39;&#39;-Substituted alkaloids of the cinchona series, especially 2&#39;&#39;substituted quinine, quinidine, cinchonine, cinchonidine and their dihydro analogs, and their salts, are prepared by treating ar-N-oxides of the alkaloids with the corresponding organometallic reagent and, if desired, converting the free bases thus formed into pharmaceutically acceptable acid addition salts. The new compounds are pharmacologically active, especially antimalarially and anti-arrhythmically.

United States Patent [191 Yardley et al.

[451 June 18, 1974 Z-SUBSTITUTED-CINCHONA ALKALOIDS [75] Inventors: John P. Yardley, King of Prussia;

Royal E. Bright, Philadelphia; Richard W. Rees; Herchel Smith, both of Bryn Mawr, all of Pa.

[73] Assignee: American Home Products Corp.,

New York, NY.

[22] Filed: Feb. 29, 1972 [21] Appl. No.: 230,467

Related US. Application Data [60] Division of Ser. No. 27,119, April 9, 1970, Pat. No. 3,643,552, which is a continuation-in-part of Ser. No. 692,277, Dec. 21, 1967, abandoned.

[52] US. Cl. 260/284 [51] Int. Cl C07d 43/24 [58] Field of Search 260/284 [56] References Cited UNITED STATES PATENTS 3,663,552 5/1972 Yardley ct al. 260/284 OTHER PUBLICATIONS Yardley et al. in Chem Abstr. Vol. 74, 86154r Abstracting Jour. Med. Chem. Vol. 14, p. 62-65 (1971 Primary EtaminerDonald G. Daus Attorney, Agent, or Firm-David E. Frankhouscr [57] ABSTRACT 9 Claims, No Drawings Z-fiUBSTITUTED-CINCHONA ALKALOIDS This application is a divisional of application Ser. No. 27,l l9, entitled 2'-Substituted-Cinchona Alkaloids,

filed Apr. 9, 1970 now U.S. Pat. No. 3,643,552, which in turn is a continuation-in-part of application Ser. No. 692,277, entitled 2'-Substituted-Cinchona Alkaloids," filed Dec. 21, 1967 now abandoned.

This invention relates to 2'-substituted cinchona alkaloids. More particularly, it is concerned with novel 2'-substituted derivatives of quinine, quinidine, dihydroquinine, dihydroquinidine cinchonine, cinchonidine, dihydrocinchonine, dihydrocinchonidine, and the like. The new compounds, and their salts, possess valuable pharmacological properties, especially antimalarial activity and anti-arrhythmic activity.

DESCRIPTION OF THE INVENTION The new compounds of this invention are selected from those of Formula (I) or (II).

I II

or pharmaceutically-acceptable acid addition salts thereof, wherein Q is a radical of the formula R is hydrogen or methoxy, R is (lower)alkyl, (lower- )alkenyl, (lower)alkynyl, [(lower)alkyl] N(CH wherein n is from 3 to 10, cyclo(lower)alkyl, halo (lower)alkyl, or halo(lower) alkenyl; and R is ethyl or vinyl, provided, however, when R is methoxy in Formula (I), R is other than phenyl.

Special mention is made of particularly important compounds of this invention. These compounds of Formula (II) wherein R is hydrogen or methoxy, R is lower (alkyl), cyclo(lower) alkyl, or [(lower)alkyl] N(CH wherein n is from about 3 to about l0; and R is ethyl or vinyl.

Especially useful embodiments of this invention are:

2'-methylquinidine, a compound of Formula (II), wherein R is methoxy, R is methyl and R is vinyl, either as the free base or as the acid addition salt with hydrogen chloride;

2-ethylquinidine, a compound of Formula (II), wherein R is methoxy, R is ethyl and R is vinyl, either as the free base or as the acid addition salt with hydrogen chloride;

2-isopentylquinidine, a compound of Formula (ll), 'wherein R is methoxy, R is isopentyl and R is vinyl,

either as the free base or as the acid addition salt with hydrogen chloride;

2'-[(dimethylamino)-n-propyl]quinidine, a compound of Formula (II), wherein R is methoxy, R is dimethylamino-n-propyl and R is vinyl, either as the free base or as the acid addition salt with hydrogen chloride;

2-t-butylquinidine, a compound of Formula (II), wherein R is methoxy, R is t-butyl and R is vinyl, either as the free base or as the acid addition salt with hydrogen chloride;

2'-n-propyldihydroquinidine, a compound ofv Formula (ll), wherein R is methoxy, R is n-propyl and R is ethyl, either as the free base or as the acid addition salt with hydrogen chloride.

Those skilled in the art will recognize that the instant compounds are 2'-substituted derivatives of the cinchona alkaloids. Thus, quinine, dihydroquinine, cinchonidine and dihydrocinchonidine are the parent substances for the instant compounds of Formula (I); and quinidine, dihydroquinidine, cinchonine and dihydrocinchonine are the parent substances for compounds of Formula (II). These alkaloids provide valuable starting materials for the instant compounds, as will be outlined in detail hereinafter.

When used herein and in the appended claims, the term lower(alkoxy) contemplates hydrocarbonoxy radicals, straight and branched chain, containing from about one to about six carbon atoms, and includes methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, tbutoxy, n-pentoxy, n-hexoxy, 2-methylpentoxy, and the like. The term (lower)alkyl contemplates hydrocarbon radicals, straight and branched chain, containing from about one to about six carbon atoms, and includes methyl, ethyl, n-propyl, i-propyl,. n-butyl, t-butyl, n pentyl, n-hexyl, 2-methylpentyl, and the like. The term (lower)alkenyl" contemplates monoand di-olefinic hydrocarbon radicals, straight and branched chain, containing from about two to about six carbon atoms, and includes vinyl, 2-methyl-2-butenyl, isopropenyl, 1,3-butadienyl, 2-pentenyl, 3-hexenyl and the like. The term (lower)alkynyl contemplates monoand diacetylenic hydrocarbon radicals, straight and branched chain, containing from about two to about six carbon atoms, and includes ethynyl, propargyl, 2-butynyl, 1,3- butadynyl, 2-pentynyl, 3-hexynyl and the like. The term cyclo(lower)alkyl contemplates saturated cyclic hydrocarbon radicals containing from about three to about six carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term halo when used by itself or in association with (lower)alkyl, (lower)alkenyl or aryl contemplates halogens, and includes fluorine, chlorine, bromine, and iodine. As will be readily apparent to those skilled in the art, compounds of Formulae (I) and (II) are bases and react with and form useful salts with organic and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, lactic, succinic, maleic, aconitic, pthalic, tartaric, and the like. These salts are especially useful to prepare soluble pharmaceutical dosage forms. in addition, certain of them are more rapidly absorbed than the free bases, permitting quicker onset of action and higher blood levels.

The compounds of this invention can be prepared in several different ways. One especially convenient manner comprises reacting a mono-ar-N-oxide of Formula (III) or (IV) wherein-R and R are as hereinabove defined, with an organomagnesium halide of the formula wherein R is as hereinabove defined and X is chloride, bromide or iodide, until formation of the Grignard adduct corresponding to Formula (I) and (ll) is substantially complete, decomposing said adduct with water or an acid such as hydrogen chloride or an obvious chemical equivalent thereof, such as ammonium chloride, and recovering the free base compound of Formula (I) or (ll), or, if desired, converting the free base, by reaction with an organic or inorganic acid into an acid addition salt, and recovering the said salt.

The mono-ar-N-oxides of Formulae III or N can be prepared by treating the corresponding alkaloid with hydrogen peroxide in glacial acetic acid by the method of M. lshikawa et al., Skika Zairo Kenkyusho Hokoku 2, l8l-l88( i961) or alternately by the method of E. Ochiai,.l. Pharm. Soc. (Japan) 68, 109 (1948). The organomagnesium halides are easily prepared by methods well known to those skilled in the art. In this connection, reference is made to the compilation in Kharash and Reinmuth, Grignard Reactions of Non'Metallic Substances," Prentice-Hall, lnc., New York, E954, and to the specific references cited therein.

In proceding according to the above method, the process is normally conducted in benzene-ether mixture at the reflux point, conditions which normally insure a homogeneous reaction mixture but other solvents or combinations with tetrahydrofuran, dioxane, toluene, and the like, can be used. Brief, for example, -45 minute, reflux periods appear to offer optimum reaction conditions.

An alternative and often useful method for preparing the compounds of this invention consists in treating N- oxides of Formula (H1) or (IV) with the corresponding organo lithium compounds of the formula R Li Conversion of the free bases of Formula (l) or (H) to the corresponding acid addition salt is accomplished by treating a solution of the base in a solvent, such as a lower alcohol, i.e., methanol or isopropanol, a ketone, such as acetone or an ether, such as diethyl ether, with the stoichiometrically equivalent amount of the desired acid, then evaporating the solvent, leaving the salt as a residue. If desired, it can be recrystallized from a solvent, such as a lower alcohol or a ketone or mixtures of such solvents.

The dihydroquinine and dihydrocinchonidine of Formula (l) and the dihydrocinchonine and dihydroquinidine of Formula (ll) may also be prepared by hydroge' nating the corresponding quinine, cinchonidine, cinchonine or quinidine. This hydrogenation is accom plished by conventional means of hydrogenating ethenoid unsaturation, for example, by dissolving unsaturated compounds or acid addition salts of Formula (I) or (ll) in a suitable solvent, i.e., methanol, which is added to palladized charcoal and reacted with hydrogen at a temperature of about 5C to about 50C, preferably at low to moderate pressures, e.g., from about 1 to about 3 atmospheres, preferably about l atmosphere until absorption of the equivalent amount or a slight excess, e.g., up to about 1.1 moles of hydrogen is substantially complete. The catalyst used is preferably a noble metal catalyst, finely divided or supported, on a carrier, for example, platinum or palladium, or palladium on carbon or palladium on charcoal. Following hydrogenation, the product is recovered by conventional means, i.e., filtering off the catalyst and taking the illtrate to dryness, dissolving the residue in water and basifying with a base (i.e., NaOH) and extracting with an organic solvent (i.e., CHCl and crystallizing the residue from an appropriate solvent (i.e., ethyl alcohol).

As is mentioned hereinabove, the new 2-substituted cinchona alkaloids of Formula I and ll, and their salts, of this invention have been found to possess useful pharmacological properties, especially as anti-malarials and as arrhythmic agents. This makes them useful in the treatment of conditions in the living organism responsive to administration of active antimalarial agents, such as the symptoms caused by malaria. in addition, they are also useful to treat conditions in the living organism responsive to administration of active antiarrhythmic agents, such as cardiac arrhythmia. Such agents are effective for the treatment of auricular fibrillation by restoring natural rhythm. Furthermore, the instant compounds are of particular value for such purposes because they exhibit excellent response, have a rapid onset of action and relatively low toxicity.

The compounds of this invention can be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, selected route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk, sugar, certain types of clay, and the like. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups, flavoring agents and dyes; and then dehydrated sufficiently to make the mixture suitable for pressing into a solid, compact form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they be injected parenterally, that is intramuscularly, intravenously or subcutaneously. For parenteral adrninistration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound selected. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages, substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects. For cardiac arrhythmias they are used preferably at a level that is in the range of from about 0.1 mg/kg to about 30 mg/kg per day, although as mentioned, variations will occur. For anti-malarial purposes they are used preferably at a level that is in the range of from about 5 mg/kg to about 600 mg/kg per day, although as mentioned, variations will occur. However, a dosage level that is in the range of from about mg/kg to about 100 mg/kg per day is most desirably employed in order to achieve most effective results.

Anti-malarial activity was measured against P. berghi in mice and P. gallinaceum in chicks by methods similar to those described by T. S. Osdene, P. B. Russell and L. Rane, J. Med. Chem, 10, 431 (1967) as follows} Mice are infected with a lethal dose of Plasmodnim berghi 3 days prior to the administration of the compound at each of three dose levels. The compound test is mg/kg of body weight. Routinely, the compounds are administered subcutaneously in oil. The mean survival time of infected control mice is 7.0 i 5.0 days. Extension of survival time of chemically-treated mice is interpreted as evidence of anti-malarial activity,

In the chick test, 9-12 day-old white Leghorn cockerels of uniform stock, which are delivered to the laboratory when 1 day old and then maintained under standard conditions, including a non-medicated diet, until ready for test. Chicks on test are given intravenous injection of 0.2 ml. of heparinized hearts blood infected with Plasmodium gallinaceum and having a minimum of 80-90 percent parasitized red blood cells. The parasitized blood is drawn by cardiac puncture from donor birds infected 72 hours earlier with Plasmodinn gallinaceum. Donor strains are maintained in separate groups of chicks, 14-16 days old, that also received inoculations of heparinized infected hearts blood. In each experiment 100 percent of the untreated controls die within 72-96 hours post-infection. In order to check factors such as changes in infectivity, or in susceptibility of the host, or to detect technical errors, a group of infected animals treated with chloroquine at dose levels producing definite increases in survival time is included as a positive control in every experiment.

Candidate compounds are dissolved or suspended in peanut oil. Treatment in the chick consists of a single dose administered either subcutaneously or orally immediately after infection. Each experiment is done with graded doses, and increases in dose levels of highly active compounds are followed by increases in survival times. If an active drug is toxic for the host, its toxicity is a limiting factor to changes in dosages. Deaths that Anti-arrythmic activity was tested by a standard pharmacological procedure similar to that described by G. S. Dawes, Brit. J. PharmacoL, l, (1946).

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples are given by way of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the scope and spirit thereof.

EXAMPLE I 2-Methylquinidine and Hydrochloride Quinidine ar-N-oxide (2.0 g, 5.9 X 10' moles) in 40 ml. of anhydrous benzene is added dropwise to a stirred solution of methyl magensium iodide in ether (25 ml 3M, 7.5 X 10" moles) during 15 minutes. The reaction mixture is refluxed under nitrogen for one-half hour, cooled to l0C and treated with ice-water followed by an excess of 2N HCl (some undissolved yellow solid is obtained at this stage; it is dissolved in warm water and added to the reaction mixture). The aqueous phase is separated, washed with ether and basified strongly with ice-potassium hydroxide solution. Chloroform (250 ml.) is added, the mixture is stirred vigorously for a few minutes and filtered through filter aid. The precipitate and filter aid are reextracted with chloroform, filtered and washed with chloroform. The chloroform layer is separated from the aqueous filtrate, washed with brine and dried (K CO Evaporation of the chloroform affords 2.1 g residue, readily crystallizing on trituration with methanol to give 2-methylquinidine (1.5 g) mp. C (as the methanol solvate). NMR:2.56 (3H singlet, 2'-methyl), 3.45 (3H singlet) methanol solvate, 3.82 (3H singlet, 6'CH O) and no absorption below 8 ppm as in quinidine, 8.50 (1H doublet, J=4.5 cps, 2-H) or quinidine ar-N-oxide 8.48 (1H doublet, J=l0 cps; 2-H). The analytical sample (from methanol) mp. C loses methanol of solvation. After drying for 5 hours, at 80C in vacuo, the product is analyzed.

Analysis for C, H N,O

Calculated C, 74.52; H, 7.74; N, 8.2 Found N, 8.3

Calculated Found C, 60.55: H, 6.91; N, 6.74; Cl, 17.05 C, 60.41; H, 7.08; N, 6.64; C1. 15.07 C, 60.61 H, 7.04

EXAMPLE ll 2'-Ethylquinidine and Hydrochloride Quinidine-ar-N-oxide (10.0 g) in 200 ml of anhydrous benzene is added slowly to 3 molar ethyl magnesium bromide in ether (125 ml) under nitrogen. The mixture is refluxed for one-half hours, chilled to C and an ice-water slurry is added cautiously. when the decomposition is complete, 2N HCl is added to acidify the mixture. The precipitate which remains is dissolved by addition of more water. The layers are separated and the aqueous phase washed once with ether. The combined organic phases are back-washed once with a small quantity of 2N HCl which is added to the aqueous phase. This is then made strongly basic by the addition of an ice-aqueous KOH mixture and filtered through filter aid. The filter cake is washed exhaustively with a CHCl zMeOH (1:1) mixture. The layers in the filtrate are separated and the aqueous phase extracted three time with CHC1 The combined organic phase is washed with brine, dried over K CO and stripped to a glass under high vacuum. The title compound is obtained as crystals from heptane 0.40 g) m.p. l35l 39C. The analytical sample is crystallized from heptane, m.p. l38-l40C; )t f 3.48, 6.19, 6.26,

6.42, 6.67 NMR: 3 proton triplet at 81.23 (CH;, of 2 ethyl group), 3 proton singlet at 83.81 (methoxy group), multiplet 84.8-6.3 (vinyl group OH), singlet at 87.14, 7.30, 7.45, doublet at 87.90 (4 aromatic protons).

Analysis for CnHggNgOg Calculated C. 74.96; H, 8,01; N, 7.95 Found C, 75.10; H, 8.31; N, 7.95

2'-Ethylquinidine hydrochloride (amorphous solid); A 3.16 (broad) 3.50, 3.93 (broad), 4.30 (shoulder) 6.20, 6.69, 6.8851.) is prepared from the base by the procedure in Example 1. Recrystallized from isopropyl alcohol and ethyl ether gives a mp l71-175C.

EXAMPLE lll 2-n-Propylquinidine and Hydrochloride Analysis for C H N,OyH,O

Calculated Found 60.38; H, 7.49; N, 6.12; Cl, 15.52 60.60: H, 7.23; N, 614; C1, 15.92

EXAMPLE 1V 2'-lsopentylquinicline and Hydrochloride Following the procedure of Example 11, using isopentyl magnesium bromide, a yield of 17 percent of the amorphous title compound is provided. Following the procedure of Example I, the amorphous title compound is converted to its dihydrochloride, a crystalline compound, m.p. l-1 74C.

Analysis for C H N O,2HCl -%H,O

Calculated C, 62.62; H, 7.85; N, 5.84; Cl, 14.79 Found C, 62.54; H, 7.53; N, 5.83; Cl, 14.50

EXAMPLE V 2 -Dimethylamino-n -propylquinidine EXAMPLE V1 The procedure of Example I is repeated, substituting for the methyl magnesium iodide, stoichiometrically equivalent amounts of the following organo magnesium halides from which are provided the corresponding 2'-substituted-quinidines:

Cl-l MgCl, 2'-methylquinidine;

Cl-l MgBr, 2'-methylquinidine;

HC 5 C MgBr, 2'-ethynylquinidine;

CH Cl-l MgCl, 2'-ethylquinidine;

Cl-l C E CMgBr, 2-prop-l-ynylquinidine;

H C%THCH MgCl, 2'-prop-2-enylquinidine;

CH CH Cl-l MgCl, 2'-propylquindine;

(Cl-l CHMgCl, 2'-isopropylquinidine;

H C- -CHC E CMgBr, 2'-but-l'yn-3-enylquinidine;

CH CH C CMgBr, 2-but-l-ynylquinidine;

H C=CHCH CH MgBn 2'-but-3-enylquinidine;

H C=C(CH )CH MgBr, 2-(2-methylprop-2- enyDquinidine;

CH (CH CH MgCl, 2'-butylquinidine;

CH (CH CH MgBr, 2-pentylquinidine;

3)2 g)3MgCl, 2-[3-(dimethylamino)- propyl quinidine;

alz -l zhu g decyl lquinidine;

2'-[ l0-(dimethylamino) 9 3( 2)4 2]2 2)t g ylamino)butyl]-quinidine;

C l-l MgBr, 2'-cyclopentylquinidine; C l-l MgBr, 2'-cyclohexylquinidine;

EXAMPLE VII The procedure of Examples I and II are repeated, substituting for the quinidine ar-N-oxide, stoichiometrically equivalent amounts of the cinchona alkaloid ar- N-oxides derived from dihydroquinidine, cinchonine, dihydrocinchonine, quinine. dihydroquinine. cinchonidine and dihydrocinchonidine. providing the following 2-substituted cinchona alkaloids:

2'-methyldihydroquinidine;

2-ethyldihydroquinidine;

2-methylcinchonine;

2'-ethylcinchonine;

2'-methyldihydrocinchonine;

2'-ethyldihydrocinchonine;

2'-methylquinine;

2'-ethylquinine;

2-methyldihydroquinine;

2-ethy1dihydroquinine;

2'-methylcinchonidine;

2'-ethylcinchonidine;

2'-methyldihydrocinchonidine;

2'-ethyldihydrocinchonidine;

The compounds are transformed into their respective acid addition salts by the procedure of Example 1.

EXAMPLE VIII Following the procedure of Example I, but substituting for hydrogen chloride, stoichiometrically equivalent amounts of fumaric acid, malic acid, citric acid, tartaric acid, embonic acid, acetic acid, sulfuric acid and phosphoric acid, then freeze-drying the reaction mixture, the corresponding acid addition salts of 2'- methylquinidine are obtained as residues. In a similar manner, the corresponding acid addition salts of 2'- ethylquinidine is prepared.

Following the above procedure, the new 2'- substituted alkaloids of Examples III and IV are converted to the corresponding fumarates, maleates, citrates, tartrates, embonates, acetates, sulfates and phosphates.

EXAMPLE IX 2-Cyclopropylquinidine and Hydrochloric Acid Addition Salt To a solution of cyclopropyl lithium in diethyl ether (2-50 m1), prepared from lithium (4.475 g, 646 mmoles) and cyclopropyl bromide (36.7 g, 331 mmoles) [Seyforth and Cohen, J. Organometal Chem., 1, 15 (1963)] is added while stirring at 5C under nitrogen a solution of quinidine-ar-N-oxide (10.0 g, 29.5 mmoles) in benzene (200 ml). When the addition is complete stirring under nitrogen is continued while allowing the reaction mixture to warm to room temperature over a period of one hour. The reaction is then stopped by chilling to 0-5C, adding ice-water and then 2N I-ICl to dissolve the precipitate. The small amount of tar remaining is dissolved in a minimum amount of methanol which is added to the main two phase mixture. The layers are then separated, the aqueous phase is washed once with a small quantity of ether, then made basic with cold 50 percent NaOH solution and then extracted thoroughly (5 times) with chloroform. The combined chloroform extracts are washed with saturated brine, dried over K CO and solvent removed in vacuo to yield a dark tar which is chromatographed through a column of activated magnesium silicate. Fractions eluted with mixtures of 1 percent methanol in chloroform and 2 percent methanol in chloroform yield the title product as the crystalline free base (from heptane), m.p. 59-72C; A 3.45, 6.15, 6.22, 6.39, 6.64, 6.88 1. Mass spectrum, M+ at 364 m/e peaks at 136 m/e (characteristic for quinuclidine fragment [Budzikiewicz. Djerassi, Williams, Structure Elucidation of Natural Products by Mass Spectrometry, Volume 1, page 220]), M- 15 m/3 (methylene proton from rearrangement of cyclopropyl group), M 40 m/e (loss of cyclopropyl less a proton). M- m/ (quinoline CI- I(OH) cyclopropyl proton- CH O). NMR signals at 1.04 and 0.95 (multiplet) ppm. Confirm presence of cyclopropyl.

The free base 1.5 g) is converted to the dihydrochloride (1.76 g) m.p. 174.8C: )t 2.96-3.10, 3.45, 3.87 (broad), 4.25 (shoulder), 6.05, 6.14, 6.62, 6.81, 6.99 1. by the procedure described in Example 1.

EXAMPLE X 2'-t-Butylquinidine and Hydrochloride Following the procedure of Example 1X using lithiot-butyl in place of the lithio-cyclopropyl, a yield of 1 1 percent of the title compound is provided. Following the procedure of Example I, the title compound is con verted to its crystalline dihydrochloride, C l'l N O 2I-ICI, mp. 240C, with a calculated m/e for the free base of 380. Experimentally, a m/e for the free base of 380 is confirmed.

EXAMPLE XI 2-n-Propyldihydroquinidine and Hydrochloride Analysis for C H N 1 Calculated Found C, 74.96; H, 8.75; N. 7.60 C, 74.78; H, 8.66; N, 7.31

Using a procedure similar to that described in Example I, the dihydrochloride salt of the title compound is provided, m.p. 184-l 86C.

EXAMPLE XII Following the procedures set forth in Example XI (dihydrogenation), 2'-substituted-quinidine compounds of Example VI are converted into the following compounds:

2-(3,3,3-trifluoropropyl)dihydroquinidine;

2- 3-( dimethylamino )propyl dihydroquinidine;

2-cyclohexyldihydroquinidine;

Following the procedure of Example I, the above compounds are converted to their respective acid addition salts with hydrogen chloride.

EXAMPLE Xlll or a pharmaceutica llv acceptahle acid addition salt thereof, wherein Q is a 4-quinolyl radical of the formuia wherein R is hydrogen or methoxy; R is (lower)alky], cyclo (lower)alkyl, or i(lower)alkyl] N-(CH wherein said (lower)alkyl has from one to six carbon atoms, said cyclo (lower)alkyl group has three to six carbon atoms, and n is from 3 to 10. a

2. The compound as defined in claim I which is 2'- methylquindine.

3. The compound as defined in claim 1, which is 2- ethylquinidine.

4. The compound as defined in claim 1, which is 2'- cyclopropylquinidine.

5. The compound as defined in claim 1, which is 2-npropylquinidinei 6. The compound as defined in claim 1, which is 2- isopentylquinidine.

7. The compound as defined in claim 1, which is 2'- dimethylamino-n-propylquinidine.

8. The compound as defined in claim 1, which is 2'-tbutylquinidine.

9. The compound as defined in claim 1, which is 2-npropyldihydroquinidine, 

2. The compound as defined in claim 1 which is 2''-methylquindine.
 3. The compound as defined in claim 1, which is 2''-ethylquinidine.
 4. The compound as defined in claim 1, which is 2''-cyclopropylquinidine.
 5. The compound as defined in claim 1, which is 2''-n-propylquinidine.
 6. The compound as defined in claim 1, which is 2''-isopentylquinidine.
 7. The compound as defined in claim 1, which is 2''-dimethylamino-n-propylquinidine.
 8. The compound as defined in claim 1, which is 2''-t-butylquinidine.
 9. The compound as defined in claim 1, which is 2''-n-propyldihydroquinidine. 